Just a handful of genetic mutations can turn bird flu into a highly infectious pathogen that could wreak havoc on humans, according to a new paper published today. It’s the first of two controversial virus mutation papers to get its day in the sun, and it shows how the H5N1 flu could evolve to infect mammals.

To test the virus, researchers led by Masaki Imai and Yoshihiro Kawaoka of the University of Wisconsin-Madison combined elements of avian flu with a recent pandemic human flu, the 2009 variant of H1N1 (you may know it as the swine flu). The new flu was capable of passing from experimental ferret to ferret through the air. (Ferrets are considered the best animal model of how flu works in humans.) The sick ferrets lost weight and had respiratory lesions, but they did not die.

"The findings described here will advance our understanding of the mechanisms and evolutionary pathways that contribute to avian influenza virus transmission in mammals," the authors write.

To understand what’s so dangerous about this virus, it helps to understand a bit about how the flu and its variants work. The name describes the molecular components of the virus; so H5N1 flu, for example, is a variant with type 5 hemagglutinin and type 1 neuraminidase proteins.

Humans have no immunity to flu viruses with a type 5 hemagglutinin. If it were to spread among people, a pandemic would likely ensue. But while H5N1 flu has been around in poultry for at least 16 years, there are only a handful of reports of human cases. The human cases have been unusually severe — at least compared with other animal-transmitted flu viruses — but the lack of a human-to-human transmission raised some questions about whether this flu could really adapt to infect us. Perhaps the H5 protein didn’t work very well in mammalian cells.

This research helped answer that question. Not only could an H5 flu indeed mutate to become transmissible among mammals, it only required four mutations to do so.

The researchers carefully figured which mutations would help the virus shift to a variant that would thrive in humans. Their paper is freely available online today, published by the journal Nature.

The scientists are also careful to note that their mutant virus possessed many human-virus traits, which might not exist in any naturally evolving H5 virus. What’s more, H5 viruses lack certain amino acids that would help them reproduce in mammals. And it’s not clear that the virus, if it evolved to infect humans on its own, would follow a similar pathway. Still, the crucial point is that it didn’t take very much mutation at all.